The LARAMED Project: Status and perspectives€¦ · The four stages of SPES project 3 Cyclotron...
Transcript of The LARAMED Project: Status and perspectives€¦ · The four stages of SPES project 3 Cyclotron...
J. Esposito, October 11, 2016 1
The LARAMED Project: Status and perspectives
J. Esposito, on behalf of LARAMED collaboration
III International SPES workshop LNL, October 11th, 2016
J. Esposito, October 11, 2016
Contents
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• Why LARAMED project: a brief recall
• LARAMED facility infrastructure set-up
• LARAMED radionuclides of interest research ongoing
program
• Emergency radionuclides of interest for theranostic
applications
• 64Cu/ 67Cu production with high-performance cyclotron
J. Esposito, October 11, 2016
a
d
b
g
The four stages of SPES project
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Cyclotron and related infrastructure
Radionuclides for health and research
Radioactive Ion beam facility
AB neutron sources for applied physics and industry
SAT underway:
LAR
AM
ED
InfrastructureSetting up
Infrastructuresetting up
Facilitydesign study
J. Esposito, October 11, 2016
Why LARAMED
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― Share our facility with different scientific and trade communities is a must nowadays (e.g. TRIUMF, JAEA,LANSCE etc. already do it
― Social recognition of the nuclear physics role for human health is an important bonus for INFN as a research institution
― External funds from radioisotopes research activities are a must for the future running of SPES/LARAMED facility
― Interesting nuclear science & technology research center dedicated both to nuclear medicine and applied physicsR&D activities (e.g. INFN research projects)
― The big Challenge: is INFN ready for partnership with private enterprises?
J. Esposito, October 11, 2016
How LARAMED Project is planned
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LAboratory of RAdionuclides for MEDicine, granted as“competitive project” at national level includes:
– A research laboratory (RILAB), owned jointly by INFN and CNR for:
• Nuclear cross section measurements (i.e. standard stack-foils activationtechnique)
• A proving ground for high power target tests
• Low-activity-production of experimental radioisotopes/radiopharmeceutical(99mTc, 64Cu, 67Cu, 89Zr, 47Sc...)
– A production facility (RIFAC), operated by INFN and a private partner, to supply market demands for parent nuclides 82Sr/82Rb and 68Ga/68Ge generator systems
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The new 70 MeV, 750µA proton driver
The brand new B70 cyclotron: Installed in May 2015, now under commissioning
Dual simultaneously beam extraction cyclotron (EP = 35-70 MeV):
1° - nuclear physics research on RIBs (SPES project) : E=40 MeV , I=200 µA (and future upgrades)
2° - applied physics (LARAMED project, neutron source) : E=35-70 MeV , I=300 µA (upgrade 500µA)
J. Esposito, October 11, 2016
RIFAC beam lines
RILAB beam line
SPES ISOL-1SPES ISOL-2ANEM, QMN
n-sources
SLOWNEn-sources
The SPES building (-1 floor): 3D layout
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J. Esposito, October 11, 2016
Final layout and cyclotron beams sharing foreseen
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RILABRIFAC
SPES building -1 level
RIFACProduction facility with
private company
RILABResearch facility on
radioisotope
ISOL1 ISOL2
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Second floor
SPES building +2 level
RILAB future laboratories layout
Radiochemistry labHot cells
Targetry lab
Radionuclide Purification lab
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Waiting for a dedicated beam-line and available laboratories, we are
collaborating with:
ARRONAX facility (Nantes, France). 70 MeV multi-particle cyclotron
St. Orsola Hospital (Bologna, Italy). 16 MeV cyclotron routinely used for 18FDG
University of Ferrara (Italy). YAP-(S)PET-CT small-animal imaging system
National Research Council (CNR) in Milan (Italy). Facility for cellular and pre-clinical studies
At LNL we already use γ-spectroscopy laboratory fully equipped with HPGe detectors and
technologies for metal vapour deposition, brazing, surface treatment (Material Science lab.).
LARAMED External Collaboration Network
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INFN already funded/running projects Project name
Tc-99m/Mo-99 direct production routes using accelerators APOTEMA (2012-2014)TECHN-OSP (2015-2017)
Participation to IAEA ' Coordinated Research Project ' (CRP) on“Alternative, non HEU-based, Tc-99m/Mo99 supply” (PI: J. Esposito)
CRP (F22062)(2011-2015)
Cu-67/Sc47 new (i.e. more efficient) production routes COME (2016)PASTA (proposal)
Participation to IAEA ' Coordinated Research Project ' (CRP) on “Radiopharmaceuticals Labelled with New Emerging Radionuclides Cu-67, Re-186, Sc-47”
CRP (F22053)(2016-2019)
Sr-89 production with ISOL technique SPES/ISOLPHARM
RILAB laboratory infrastructure set upLARAMED comp. project (2013-2016)
High Power Target concepts R&D (64/67Cu)TERABIO comp. project
(2016-2019)
Running R&D activities within LARAMED framework
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Radioisotope Half-life
Sc47 3.35 d
Cu-64 12.7 h
Cu-67 2.58 d
Sr-82 25.4 d
Ge-68 270.8 d
Tc99m 6.01 h
Sr-89 50.5 d
Starting radionuclides of interest for nuclear medicine. They can beproduced by means of the SPES cyclotron. Additional ones are underexamination
LARAMED first radionuclides list of interest
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J. Esposito, October 11, 2016
82Sr/82Rb: heart function tracer
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• This radioisotope is actually produced in a limited amount in few accelerator facilities worldwide
Isotope Sr-82 Rb-82
t 1/2 25d 1.27m
EC 100% in Rb82 -
b+ - 100%
b- - -
• The ion Rb+ is a biologicanalog of K+, fundamental inthe heart cell operation.
• Once administered byintravenous injection, 82Rb+ g
emitter radioisotope, can beused as tracer to study thereal-time heart functions
J. Esposito, October 11, 2016
68Ge/68Ga: many pathologies tracer
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• Together with F‐18 e C‐11, recently, therequest of the β+ emitter radionuclide 68Gahas grown exponentially
• Ga‐68 proved to be stably labelled to smallpeptidic biomolecules, used in thediagnosys of many pathologies of peptidereceptor tissues
Isotope Ge-68 Ga-68
t 1/2 271d 68m
EC - -
b+ - 100%
b- 100% in Ga-68
-
• The production, by means of medium-highenergy cyclotrons, will provide an effectivesolution to the problem of availability ofthe generator nuclide 68Ge, whoseproduction, with the methods usednowadays, is not enough
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90% of all nuclear medicine (NM) studies involve diagnostic imaging;
Quasi-ideal radioisotope for imaging: main properties
o Suitable (soft 140.5 keV) γ energy
o Nearly pure gamma emitter
o Proper half-life
o versatile and well-known chemistry
o β- decay product of 99Mo (66 h half-life)
good image quality, low radiation dose to the patient
label various molecules
for medical examination
Currently available on the market under theMo-99/Tc-99m generators
• 99mTc use: ~80% (>30 million procedures per year)
• 18F use: ~10%;
• rest others one study every second !!!!!
Why interested in 99mTcTc‐99m: the workhorse of modern medical imaging
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Tc99m supply World crisis: seeking for alternative routes
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Published online 15 July 2009 | Nature 460,
312-313 (2009) | doi:10.1038/460312a
Published online 23 October 2008 | Nature |
doi:10.1038/news.2008.1186
Published online 12 February 2010 |
Nature | doi:10.1038/news.2010.70 Published online 12 December 2013 |
Nature doi:10.1038/504202a
Published online 12 September 2016 |
Nature ! doi:10.1038/nature.2016.20577
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APOTEMA/TECHNOSP exp.: INFN contribution (2012-2017)
Main project goalAssessment of accelerator-driven alternative production of 99mTcexploting the SPES proton cyclotron at LNL
Current supply route 99Mo parent production in a few nuclear reactor sites in theworld, as fission fragment product in high-enriched U235«weapon grade» fissile material
Optimal production (direct route):
1. Ep ~ 18-20 MeV max
2. 100Mo(>99%) enriched moly targets
3. Irr. Times not longer than T1/2 (better within ½ T1/2)
By using high-performance cutting edge technology cyclotrons(i.e. 300-500 µA current intensity (eg. SPES to LNL) and energiesof up to 20 MeV) the daily needs of the entire Veneto region(273 GBq/day = ~ 7 Ci/day) may be supplied if necessary
Laboratori Nazionali di Legnaro
100Mo(p,2n)99mTc (direct route)100Mo(p,x)99Mo 99Mo/99mTc generator
Alternative Tc-99m production route
Manenti S, et al ARI, 94, (2014) 394-398
J. Esposito, Sci Tech of Nuc Inst, vol. 2013, Article ID 972381, 14 pages, 2013. doi:10.1155/2013/972381
P. Martini, et al. ARI, 118, (2016) 302-307
J. Esposito, October 11, 2016
99mTc radionuclidic purity
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• Radionuclidic purity of the 99mTc-eluate was performed with
γ-spectrometry (HPGe detector)
• Total activity of 9xTc-isotopes < 1%
• 99mTc activity at the time of SPECT imaging (about 7 hours after EOB)
RNP 99mTc > 99%
Isotope Half-life
Tc-99m 6.0067 h
Tc-93g 2.75 h
Tc-94g 4.88 h
Tc-95g 20.0 h
Tc-96g 4.28 d
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TECHN_OSP project (2015-2017): A hub and spoke approach
R&D activities aimed at an industrially-based technology for future homeland accelerator-99mTc production based on a selected cyclotrons’ network in Italy:
May the the colllaboration network gathered
around the APOTEMA research project
have a role as the strategic center for the
scientific/technical support?
IBA Cylone 18/9 protons 18 MeV, up to 100 A (1.8 kW)9 MeV, 40 A deuterons
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~1kW/cm2 new target concepts: successful tests at LNL STS lab of molybdenum layer deposition on backing material
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First successful test to deposit multiple layers
(0.5 m each) up to 300 m on a copper
backing using the Physical Vapor Deposition
(PVD) technique under UHV.
No stress at micro-structure level has been
observed.
The system has been fully automated
Further tests are underway to fully optimize the
production process able to produce good
quality layers
J. Esposito, October 11, 2016
Irradiation tests at S. Orsola Hospital
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110 μm Mo-nat directly sputtered onto Cu backing (first time ever)70µA, 15.6 MeV -> ~1.1 kW/cm2 achieved!! Contact between sputtered Mo film, and Cu-backing remains excellentDouble 3hrs irr/day -> ~1.5 Ci daily needs S. Orsola Hospital
GE PetTRACE -16 Protons: 16 MeV, up to 75 A (1.2 kW)Deuterons:8.4 MeV, 50 A deuterons
Standard production with metallic targets : <25 µA
Before
After
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Accelerator-99mTc: imaging studies
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• Anesthetized WIST rats were injected into the jugular vein
• Whole-body SPECT-CT biodistribution studies were carried out with the hybrid YAP(S)PET-CT small-animal scanner at Ferrara Univ.
• Depending on rats’ dimensions, n. 4-5 scans have been taken
*A. Del Guerra et al., IEEE Trans.Nucl.Science (2004)**G. Di Domenico et al., Nucl Instrum Meth A (2007) 571 :110–113
SPECT modality *Field of view: 4 x 4 x cm2
Yap(Ce): 4 x 4 x 3 cm3
Energy Res.: 26% (140 keV)Spatial Res.: 3.5 mmSensitivity: 15 cps/MBq
CT **Active area: 49.2 x 49.3 mm2
GOS on dual CMOS array (1024x1024 photodiodes)
X-ray tube
Det. 1 Det. 2X-ray detector
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APOTEMA: First in-vivo SPECT-CT images
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Generator-produced 99mTccorrection for injection time and activity
HMPAO MYOVIEWPertechnetate HMPAO MYOVIEWPertechnetate
Accelerator-produced 99mTccorrection for inj. Time, activity and scatter
Preliminary SPECT-CT imaging study confirmed comparable biodistribution of radiopharmaceuticals labelled with 99mTc (generator- or cyclotron-produced) The effect of scattered high-energy γ-rays strongly depends on the imaging system
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67Cu and 64Cu: new emerging radionuclides
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NuDat 2.6 database (2013) - NNDC
Cu-67 very attractive because of physical-chemical properties (T1/2 2.58 d). Suitable forTheranostic (Therapy + Diagnostic ) applications, as single isotope, or in pair with64Cu (β-emitter, half-life 12.7 h).Potential of theranostic is the selection of patients prior therapy and the use of maximum
tolerated dose (MTD)*, based on previous SPECT/CT (67Cu) or PET/CT (64Cu) diag. proc.* Srivastava SC, . J Postgrad Med Edu Res 47 (2013) 1:31-46
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Applications of 67Cu and 64Cu in nuclear medicine
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Human Copper transporter 1 (hCtr1) plays a major role in the cellular uptake of copper in humans and it is overexpressed in a variety of cancers
• 64Cu is ALREADY used in nuclear medicine for PET (diagnostic proc.)• 64Cu seems to provide excellent results also in THERAPY (under simple 64CuCl2)
*Peng F et al., J Nucl Med (2006)47:1649-1652 ; **H Cai et al. , J Nucl Med (2014) 55:622-628.
AfterBeforeMalignant melanoma images (left leg) before and after 100
mCi 64CuCl2 injection
What will it happen by using 67Cu ?o 67Cu is a promising nuclide in RAdio Immuno Therapy (RAIT)o 67Cu‘s limiting factor: LOW availability
Worldwide Production per month : only 1 patient dose (100 mCi ≈ 3.7 GBq)
67Cu production: Goal for both LARAMED and ARRONAX !
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67Cu current production route
In order to have a pure 67Cu (RNP>99%) it is necessary to wait that 64Cu decays
lose ≈ 80% of 67Cu activity
68Zn(p,2p) reaction, already used but…not efficientIAEA Technical Report Series No. 473 (2011)
67Cu monthly production: 100 mCi (@ BNL) Only ONE
therapeutic dose !
J. Esposito, October 11, 2016
Proton beam
Stacked-foil Target holder
Monitor reactions*:
EP < 50 MeV natNi(p,x)57Ni (natNi ~ 20 µm)
EP > 50 MeV 27Al(p,x)22Na (27Al ~ 20 µm)
*In
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Stacked-foil target structure
Assessment of current 68Zn(p,2p)67Cu xs data
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New 68Zn(p,2p)67Cu xs
measurements at ARRONAX
Target foils prepared at the LNL targetry lab
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Energy [keV]
Cu-67Intensity
Ga-67Intensity
91.266 5 7.0 1 3.11 4
93.311 5 16.1 2 38.81 3
184.577 10 48.7 3 21.41 1
208.951 10 0.115 5 2.46 1
300.219 10 0.797 11 16.64 12
393.529 10 0.220 8 4.56 24
494.166 15 0.0684 14
703.106 15 0.0105 9
794.381 15 0.0540 18
887.688 15 0.148 3 Chemical separation Cu/Ga is mandatory !!
Tracer: Cu-61 and Ga-66
68Zn(p,x)reactions*: co-production of 67Cu and 67Ga
67Ga interfering radionuclide
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Xs measurements at 35-70 MeV
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The 68Zn(p,2p)67Cu cross section at ARRONAX
100% enriched 68Zn
*
Results next to be issued
Optimal Energy Range: EP = 70-40 MeV
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COME (COpper MEasurement) exp.: INFN funded (2016)
Estimations based on Talys code
Best energy range: 50-70 MeV
Exp data are needed !
IAEA Technical Report Series No. 473 (2011)
No experimental data are available for EP > 35 MeV
CoMe project:70Zn(p,x)67Cu,64Cu xs measurements
5 Irradiation runs @ Arronax done during 2016 : data analysis in progress !
A new reaction route under exam.: 70Zn(p,x)67Cu
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70Zn(p,x)67Cu nuclear models diagreement
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The 70Zn(p,x)67Cu cross section ESTIMATION
0
5
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15
20
25
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35
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0 10 20 30 40 50 60 70 80 90 100
Cr
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mb
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Proton Energy (MeV)
70Zn(p,x)67Cu
Talys Default
Talys Adjusted
TENDL2014
PACE4
Cross Section Measured
E < 35 MeV
We need the support of nuclear physics community to explain this disagreement !
DiscrepancyTalys-PACE
codes
J. Esposito, October 11, 2016
The LARAMED collaboration group
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S. Todde (MI)
A. Duatti (FE)
G. Cicoria (BO)
C. Rossi Alvarez
(INFN-LNL)
THANK
YOU
J. Esposito
(INFN-LNL)
F. Haddad
(Director)
H. Skliarova
(STS lab LNL)
S. Cisternino
(STS lab LNL)
V. Palmieri
(STS lab LNL)
L. Uccelli
P. Martini
A. Boschi
M. Pasquali
L. Mou
(INFN-LNL)
G. Pupillo
INFN-LNL
G. Pupillo
INFN-LNL